Febrile seizures (FS) are the most common type of convulsive events in children. FS have been extensively studied using animal models, in which rat and mice pups are placed in a hyperthermic environment. Such work has largely focused on the consequences rather than the mechanisms of experimental febrile seizures (eFS).
We have shown that eFS are preceded by a dramatic rise in the rate of respiration (Schuchmann et al., 2006). The consequent respiratory alkalosis affecting the brain and increasing neuronal excitability is a direct cause of the eFS. If a similar mechanism contributes to human FS and other fever-related epileptiform syndromes, a number of factors operating at the molecular, cellular and systems level that have not been previously thought to be involved in their etiology must be considered. These include physiological and pathophysiological factors affecting CO2 chemosensitivity, as well as cellular and systemic mechanisms of acid-base regulation. Furthermore, a critical role for brain pH in FS points to novel types of susceptibility genes, which include genes coding pH-sensitive target proteins (e.g. neuronal ion channels) and pH-regulatory proteins.
In vitro and in vivo experiments, as well as clinical trials, outlined in this proposal are designed to study these novel ideas and putative therapies based on them.
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